Assessment of a small molecule melanocortin-4 receptor-specific agonist on energy homeostasis

2004 ◽  
Vol 1000 (1-2) ◽  
pp. 64-71 ◽  
Author(s):  
David Cepoi ◽  
Teresa Phillips ◽  
Mary Cismowski ◽  
Val S Goodfellow ◽  
Nick Ling ◽  
...  
Keyword(s):  
Small Molecule ◽  
Energy Homeostasis ◽  
Melanocortin 4 Receptor

scholarly journals Structural insights into ligand recognition and activation of the melanocortin-4 receptor

2021 ◽  
Author(s):  
Yan Zhang ◽  
Huibing Zhang ◽  
Li-Nan Chen ◽  
Dehua Yang ◽  
Chunyou Mao ◽  
...  
Keyword(s):  
Small Molecule ◽  
Energy Homeostasis ◽  
Structural Information ◽  
Sequence Similarity ◽  
Receptor Activation ◽  
Activation Mechanism ◽  
Receptor Subtype ◽  
High Sequence Similarity ◽  
Subtype Selectivity ◽  
Melanocortin 4 Receptor

Melanocortin-4 receptor (MC4R) plays a central role in the regulation of energy homeostasis. Its high sequence similarity to other MC receptor family members, low agonist selectivity and the lack of structural information concerning receptor activation have hampered the development of MC4R-seletive therapeutics to treat obesity. Here, we report four high-resolution structures of full-length MC4R in complex with the heterotrimeric Gs protein stimulated by the endogenous peptide α-MSH, FDA-approved drugs afamelanotide (Scenesse™) and bremelanotide (Vyleesi™), and selective small-molecule ligand THIQ, respectively. Together with pharmacological studies, our results reveal the conserved binding mode of peptidic agonists, the distinctive molecular details of small-molecule agonist recognition underlying receptor subtype selectivity, and distinct activation mechanism for MC4R, thereby offering new insights into G protein coupling. Our work may facilitate the discovery of selective therapeutic agents targeting MC4R.

scholarly journals Agouti-related protein (83-132) is a competitive antagonist at the human melanocortin-4 receptor: no evidence for differential interactions with pro-opiomelanocortin-derived ligands

2004 ◽  
Vol 180 (1) ◽  
pp. 183-191 ◽  
Author(s):  
LE Pritchard ◽  
D Armstrong ◽  
N Davies ◽  
RL Oliver ◽  
CA Schmitz ◽  
...  
Keyword(s):  
Energy Homeostasis ◽  
Intracellular Camp ◽  
Related Protein ◽  
Dissociation Kinetics ◽  
Competitive Antagonist ◽  
Melanocyte Stimulating Hormone ◽  
Natural Ligand ◽  
Melanocortin 4 Receptor ◽  
Significant Difference ◽  
Agouti Related Protein

Interactions between pro-opiomelanocortin (POMC)-derived peptides, agouti-related protein (AGRP) and the melanocortin-4 receptor (MC4-R) are central to energy homeostasis. In this study we have undertaken comprehensive pharmacological analysis of these interactions using a CHOK1 cell line stably transfected with human MC4-R. Our main objectives were (1) to compare the relative affinities and potencies of POMC-derived peptides endogenously secreted within the hypothalamus, (2) to investigate the potency of AGRP(83-132) antagonism with respect to each POMC-derived peptide and (3) to determine whether AGRP(83-132) and POMC-derived peptides act allosterically or orthosterically. We have found that beta melanocyte-stimulating hormone (betaMSH), desacetyl alpha MSH (da-alphaMSH) and adrenocorticotrophic hormone all have very similar affinities and potencies at the MC4-R compared with the presumed natural ligand, alphaMSH. Moreover, even MSH precursors, such as beta lipotrophic hormone, showed significant binding and functional activity. Therefore, many POMC-derived peptides could have important roles in appetite regulation and it seems unlikely that alphaMSH is the sole physiological ligand. We have shown that AGRP(83-132) acts as a competitive antagonist. There was no significant difference in the potency of inhibition by AGRP(83-132) or agouti(87-132) at the MC4-R, regardless of which POMC peptide was used as an agonist. Furthermore, we have found that AGRP(83-132) has no effect on the dissociation kinetics of radiolabelled Nle4,D-Phe7 MSH from the MC4-R, indicating an absence of allosteric effects. This provides strong pharmacological evidence that AGRP(83-132) acts orthosterically at the MC4-R to inhibit Gs-coupled accumulation of intracellular cAMP.

Maternal obesity increases hypothalamic leptin receptor expression and sensitivity in juvenile obesity-prone rats

2007 ◽  
Vol 292 (5) ◽  
pp. R1782-R1791 ◽  
Author(s):  
Judith N. Gorski ◽  
Ambrose A. Dunn-Meynell ◽  
Barry E. Levin
Keyword(s):  
Energy Homeostasis ◽  
Leptin Receptor ◽  
Maternal Obesity ◽  
Subsequent Development ◽  
Receptor Expression ◽  
Leptin Resistance ◽  
Melanocortin 4 Receptor ◽  
Time Period ◽  
Brown Adipose ◽  
Juvenile Obesity

In rats selectively bred to develop diet-induced obesity (DIO) or to be diet-resistant (DR), DIO maternal obesity selectively enhances the development of obesity and insulin resistance in their adult offspring. We postulated that the interaction between genetic predisposition and factors in the maternal environment alter the development of hypothalamic peptide systems involved in energy homeostasis regulation. Maternal obesity in the current studies led to increased body and fat pad weights and higher leptin and insulin levels in postnatal day 16 offspring of both DIO and DR dams. However, by 6 wk of age, most of these intergroup differences disappeared and offspring of obese DIO dams had unexpected increases in arcuate nucleus leptin receptor mRNA, peripheral insulin sensitivity, diet- and leptin-induced brown adipose temperature increase and 24-h anorectic response compared with offspring of lean DIO, but not lean DR dams. On the other hand, while offspring of obese DIO dams did have the highest ventromedial nucleus melanocortin-4 receptor expression, their anorectic and brown adipose thermogenic responses to the melanocortin agonist, Melanotan II (MTII), did not differ from those of offspring of lean DR or DIO dams. Thus, during their rapid growth phase, juvenile offspring of obese DIO dams have alterations in their hypothalamic systems regulating energy homeostasis, which ameliorates their genetic and perinatally determined predisposition toward leptin resistance. Because they later go onto become more obese, it is possible that interventions during this time period might prevent the subsequent development of obesity.

scholarly journals Neuropeptides in Obesity and Metabolic Disease

2018 ◽  
Vol 64 (1) ◽  
pp. 173-182 ◽  
Author(s):  
Agatha A van der Klaauw
Keyword(s):  
Neural Control ◽  
Energy Homeostasis ◽  
Energy State ◽  
Gut Hormones ◽  
Hormonal Control ◽  
Designer Drugs ◽  
Health Concern ◽  
Compensatory Mechanisms ◽  
Melanocortin 4 Receptor ◽  
Treatment Of Obesity

Abstract BACKGROUND The global rise in the prevalence of obesity and associated comorbidities such as type 2 diabetes, cardiovascular disease, and cancer represents a major public health concern. CONTENT Studies in rodents with the use of global and targeted gene disruption, and mapping of neurocircuitry by using optogenetics and designer receptors exclusively activated by designer drugs (DREADDs) have greatly advanced our understanding of the neural control of body weight. In conjunction with analytical chemistry techniques involving classical immunoassays and mass spectrometry, many neuropeptides that are key to energy homeostasis have been identified. The actions of neuropeptides are diverse, from paracrine modulation of local neurotransmission to hormonal control of distant target organs. SUMMARY Multiple hormones, such as the adipocyte-derived leptin, insulin, and gut hormones, and nutrients signal peripheral energy state to the central nervous system. Neurons in distinct areas of the hypothalamus and brainstem integrate and translate this information by both direct inhibitory/excitatory projections and anorexigenic or orexigenic neuropeptides into actions on food intake and energy expenditure. The importance of these neuropeptides in human energy balance is most powerfully illustrated by genetic forms of obesity that involve neuropeptides such as melanocortin-4-receptor (MC4R) deficiency. Drugs that mimic the actions of neuropeptides are being tested for the treatment of obesity. Successful therapeutic strategies in obesity will require in-depth knowledge of the neuronal circuits they are working in, the downstream targets, and potential compensatory mechanisms.

scholarly journals Melanocortin 4 receptor is not required for estrogenic regulations on energy homeostasis and reproduction

Metabolism ◽  
2017 ◽  
Vol 70 ◽  
pp. 152-159 ◽  
Author(s):  
Pingwen Xu ◽  
Liangru Zhu ◽  
Kenji Saito ◽  
Yongjie Yang ◽  
Chunmei Wang ◽  
...  
Keyword(s):  
Energy Homeostasis ◽  
Melanocortin 4 Receptor

Melanocortin 4 receptor ligands modulate energy homeostasis through urocortin 1 neurons of the centrally projecting Edinger-Westphal nucleus

2017 ◽  
Vol 118 ◽  
pp. 26-37 ◽  
Author(s):  
Nóra Füredi ◽  
Ákos Nagy ◽  
Alexandra Mikó ◽  
Gergely Berta ◽  
Tamás Kozicz ◽  
...  
Keyword(s):  
Energy Homeostasis ◽  
Receptor Ligands ◽  
Melanocortin 4 Receptor ◽  
Urocortin 1 ◽  
Edinger Westphal Nucleus

scholarly journals The single pass membrane protein MRAP2 regulates energy homeostasis by promoting primary cilia localization of the G protein-coupled receptor MC4R

2020 ◽  
Author(s):  
Adélaïde Bernard ◽  
Irene Ojeda Naharros ◽  
Florence Bourgain-Guglielmetti ◽  
Jordi Ciprin ◽  
Xinyu Yue ◽  
...  
Keyword(s):  
G Protein ◽  
Energy Homeostasis ◽  
Primary Cilia ◽  
Melanocortin Receptor ◽  
G Protein Coupled Receptor ◽  
Promoting Effect ◽  
Receptor Associated Protein ◽  
Extracellular Signals ◽  
Melanocortin 4 Receptor ◽  
G Protein Coupled

ABSTRACTThe G protein-coupled receptor MC4R (Melanocortin-4 Receptor) and its associated protein MRAP2 (Melanocortin Receptor-Associated Protein 2) are both essential for the regulation of food intake and body weight in humans and mice. MC4R localizes and functions at the neuronal primary cilium, a microtubule-based organelle that senses and relays extracellular signals. Here, we demonstrate that MRAP2 is critical for the ciliary localization and weight-regulating function of MC4R. Our data reveal that GPCR localization to primary cilia can require specific accessory proteins that may not be present in heterologous cell systems. Our findings also demonstrate the essential role of neuronal primary cilia localization of MC4R for adequate control of energy homeostasis and the obesity-promoting effect of genetic disruption of this pathway.

scholarly journals Evaluation of the MC4R gene across eMERGE network identifies many unreported obesity-associated variants

2020 ◽  
Vol 45 (1) ◽  
pp. 155-169
Author(s):  
Bahram Namjou ◽  
◽  
Ian B. Stanaway ◽  
Todd Lingren ◽  
Frank D. Mentch ◽  
...  
Keyword(s):  
Energy Homeostasis ◽  
Phase Iii ◽  
Risk Haplotype ◽  
Class Iii ◽  
Sequencing Data ◽  
Coding Region ◽  
Obesity Class ◽  
Mc4r Gene ◽  
Melanocortin 4 Receptor ◽  
Coding Variants

Abstract Background/Objectives Melanocortin-4 receptor (MC4R) plays an essential role in food intake and energy homeostasis. More than 170 MC4R variants have been described over the past two decades, with conflicting reports regarding the prevalence and phenotypic effects of these variants in diverse cohorts. To determine the frequency of MC4R variants in large cohort of different ancestries, we evaluated the MC4R coding region for 20,537 eMERGE participants with sequencing data plus additional 77,454 independent individuals with genome-wide genotyping data at this locus. Subjects/Methods The sequencing data were obtained from the eMERGE phase III study, in which multisample variant call format calls have been generated, curated, and annotated. In addition to penetrance estimation using body mass index (BMI) as a binary outcome, GWAS and PheWAS were performed using median BMI in linear regression analyses. All results were adjusted for principal components, age, sex, and sites of genotyping. Results Targeted sequencing data of MC4R revealed 125 coding variants in 1839 eMERGE participants including 30 unreported coding variants that were predicted to be functionally damaging. Highly penetrant unreported variants included (L325I, E308K, D298N, S270F, F261L, T248A, D111V, and Y80F) in which seven participants had obesity class III defined as BMI ≥ 40 kg/m2. In GWAS analysis, in addition to known risk haplotype upstream of MC4R (best variant rs6567160 (P = 5.36 × 10−25, Beta = 0.37), a novel rare haplotype was detected which was protective against obesity and encompassed the V103I variant with known gain-of-function properties (P = 6.23 × 10−08, Beta = −0.62). PheWAS analyses extended this protective effect of V103I to type 2 diabetes, diabetic nephropathy, and chronic renal failure independent of BMI. Conclusions MC4R screening in a large eMERGE cohort confirmed many previous findings, extend the MC4R pleotropic effects, and discovered additional MC4R rare alleles that probably contribute to obesity.

Abstract 14729: Weight Loss Reduces Atrial Fibrillation Inducibility and Burden in Severe Obesity Induced by Either High-Fat Diet or Genetic Hyperphagia in Mice

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Eleonora Savio-Galimberti ◽  
Prince Kannankeril ◽  
David Wasserman ◽  
Dawood Darbar
Keyword(s):  
Atrial Fibrillation ◽  
Morbid Obesity ◽  
Weight Loss ◽  
High Fat Diet ◽  
Energy Homeostasis ◽  
Loss Of Function ◽  
High Fat ◽  
Knock Out ◽  
Mc4r Gene ◽  
Melanocortin 4 Receptor

Introduction: Atrial fibrillation (AF), the most common sustained arrhythmia worldwide, is associated with increased morbidity and mortality. Obesity is increasingly recognized as an important risk factor to develop AF and heart disease with a diet rich in fats leading to morbid obesity. Melanocortin-4 receptor (MC4R) gene is a critical regulator of energy homeostasis, and homozygous loss-of-function mutations cause hyperphagia and morbid obesity. Hypothesis: We hypothesized that obesity and its comorbidities can create a profibrillatory substrate for AF in high fat diet-induced obese (DIO) and MC4R knock-out (MC4R-KO) mice, and that this substrate can be reversed by weight loss. Methods: Transesophageal rapid pacing was performed using atrial burst pacing (cycle length: 50-15 ms, for 15 s) to determine AF inducibility (% of mice that develop AF) and AF burden (number of AF episodes and total AF duration/mouse) in lightly anesthesized normotensive mice (C57bl6 mice [LEAN], DIO, and MC4R-KO), with continuous ECG monitoring. Transthoracic echocardiography was performed to assess right (R) and left (L) atrial appendage (AA) sizes. Results: Atrial burst pacing induced AF in 91% of DIO and 100% of MC4R-KO vs. 50% of LEAN (P<0.01, N=8 mice/group). Compared to LEAN, both DIO and MC4R-KO exhibited greater number of inducible AF episodes (0.7±0.2 vs. 1.8±0.2 vs. 1.8±0.1, P<0.01, N=15 mice/group) with longer duration (17.9±3 vs. 196±22 vs. 244±34 s, P<0.0001, N=15 mice/group; Figure). Both DIO and MC4R-KO had greater LAA volumes as compared with LEAN (5.2±0.2 vs. 6.7±0.4 vs. 4.1±0.1 μl, P<0.01, N=8 mice/group). RAA volume was similar across groups. After 20% weight loss, both AF burden and LAA volumes were significantly reduced to those seen in LEAN (22±5 s, 4.5±0.1 μl, P<0.001, N=8 mice/group). Conclusions: High-fat diet or genetic hyperphagia-induced obesity increases LAA volume and creates a profibrillatory substrate for AF that can be reversed with weight loss.

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